Is RYK p.Pro548Ser (c.1642C>T) pathogenic?

RYK p.Pro548Ser (c.1642C>T) is classified Uncertain significance in RYK (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.9726); Absent from gnomAD v4.1.

How common is RYK p.Pro548Ser (c.1642C>T) in the general population?

RYK p.Pro548Ser (c.1642C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RYK p.Pro548Ser (c.1642C>T)?

AlphaMissense predicts likely pathogenic (score 0.9726) — an in-silico prediction, not a clinical call.

RYK p.Pro548Ser

c.1642C>T · VCV3315861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9726	likely pathogenic
REVEL	0.731	pathogenic-leaning
SaProt	LLR -11.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 20 kb · p 7.2e-08 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RYK
Protein: p.Pro548Ser
Coding: c.1642C>T
MANE Select: NM_002958
Type: single nucleotide variant
Location: chr3:134159307 (GRCh38)
Gene constraint: LOEUF 0.457 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 80.54 · 1 PDB
Residue 548: an α-helix; the protein kinase domain

Full RYK gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RYK c.233-4C>G Benign ★★ same type
RYK p.Arg51Trp Benign ★★ same type
RYK p.Lys464Arg Benign ★★ same type
RYK c.355-4703C>G Uncertain significance ★ same type
RYK p.Arg424Ter Uncertain significance ★ same type
RYK p.Asp287Glu Uncertain significance ★ ⚠ same type
RYK p.Ile303Val Uncertain significance ★ ⚠ same type
RYK p.Ile325Leu Conflicting classifications of pathogenicity ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ryk-p-pro548ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown